Targeting key apoptosis regulators to overcome the apoptotic resistance of cancer cells is a highly attractive therapeutic strategy. The BCL-2 protein family includes both pro- and anti-apoptotic proteins that form a complex interaction network of checks and balances that regulate the critical balance between cellular life and death. BAX is a pro-apoptotic BCL-2 member that, when activated, undergoes a structural transformation, which converts BAX from an inactive conformation into a lethal one, creating mitochondrial pores. Although inactivating mutations in BAX have been identified with a very small frequency in tumors, significant overexpression of anti-apoptotic BCL-2 members is more common in cancer cells and contributes to tumorigenesis and chemoresistance. Therefore, the vast majority of cancer cells contain functional but suppressed BAX. Targeting BAX with small molecules has not been endeavored, since our understanding of the mechanism of pro-apoptotic BAX activation has been elusive. The recent discovery of the BAX trigger site and BAX activator molecule 7, which triggers BAX activation and selective BAX-mediated cell death through binding to this trigger site, enable the direct and rational targeting of this high-profile drug taget. Here we propose to evaluate the potential of the trigger site of BAX as a novel pharmacological strategy to reactivate cancer cell death and develop BAX activator molecules (BAMs) as potential therapeutic candidates in the context of resistant and refractory Acute Myeloid Leukemia (AML). Specifically, we will synthesize a focused chemical library of novel BAMs based on structure-activity relationship insights and in silico drug design. Compounds will be tested in a variety of biophysical assays, including fluorescence polarization and NMR spectroscopy as well as functional BAX activation assays that measure the capacity of compounds to trigger BAX conformational activation, BAX-mediated membrane parmeabilization and selective BAX-mediated cell death through a distinct mechanism. Through an iterative process of optimizing potency and selectivity, selected BAMs will be evaluated for their therapeutic potential to restore cancer cell death in AML cells and their pharmacological profile will be evaluated in mouse models of human AML. Thus, we propose a multidisciplinary approach that combines synthetic chemistry, structural biology, biochemistry, cancer cell biology and in vivo efficacy and pharmacokinetic studies to develop a novel small-molecule therapeutic approach to restore cancer cell death by directly targeting BAX and providing BAMs for future development into cancer therapeutics.